Lack of Change in the Adaptation Ability of the Bladder for the Urine Production Rate in Aged Men with Nocturia

Kira, Satoru; Mitsui, Takahiko; Miyamoto, Tatsuya; Ihara, Takeshi; Nakagomi, Hiroshi; Sawada, Norifumi; Takeda, Masayuki

doi:10.1159/000488002

Cited by 4 publications

(3 citation statements)

References 15 publications

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“…Clock Δ19/Δ19 mice have been reported to show nocturia phenotype due to the loss of circadian bladder functions, which is characterized by lower VF and higher Uvol/v in the light phase than in the dark phase in WT mice 11 . Interestingly, the differences in the characteristics of voiding behaviors and circadian changes in the serum level of PEA, 9-HODE, and 4-HDoHE between WT and Clock Δ19/Δ19 mice were in agreement with the differences observed previously between elderly patients with nocturia and those without nocturia 17,20 . This is the first study to report the relationship between nocturia and levels of fatty acid metabolites, such as PEA, 9-HODE, and 4-HDoHE in the serum.…”

Section: Discussionsupporting

confidence: 90%

Effects of fatty acid metabolites on nocturia

Ihara

Shimura

Tsuchiya

et al. 2022

Sci Rep

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Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (ClockΔ19/Δ19) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in ClockΔ19/Δ19 mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in ClockΔ19/Δ19 than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.

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Section: Discussionsupporting

confidence: 90%

Effects of fatty acid metabolites on nocturia

Ihara

Shimura

Tsuchiya

et al. 2022

Sci Rep

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“…Uvol/v was previously reported to exhibit a circadian rhythm under the regulation of clock genes in the mouse bladder, which was enhanced in the sleep phase compared to that in the active phase 2,7 . The disruption of bladder capacity differences between day and night is speculated to be one cause of nocturia that is associated with circadian clock disorders in humans 28–30 . These changes were also observed in the present study (Figs 1H and 5H).…”

Section: Discussionmentioning

confidence: 99%

Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia

Ihara

Nakamura

Mitsui

et al. 2019

Sci Rep

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Intermittent stress disrupts the circadian rhythm in clock genes such as Per2 only in peripheral organs without any effect on the central circadian clock in the suprachiasmatic nucleus. Here, the effect of restraint stress (RS) on circadian bladder function was investigated based on urination behavior and gene expression rhythms. Furthermore, PF670462 (PF), a Per2 phosphorylation enzyme inhibitor, was administered to investigate the effects on circadian bladder re-alignment after RS. Two-hour RS during the light (sleep) phase was applied to mice (RS mice) for 5 days. The following parameters were then examined: urination behaviors; clock gene expression rhythms and urinary sensory-related molecules such as piezo type mechanosensitive ion channel component 1 ( Piezo1 ), transient receptor potential cation channel subfamily V member 4 ( TRPV4 ), and Connexin26 ( Cx26 ) in the bladder mucosa; Per2 expression in the excised bladder of Per2 luciferase knock-in mice (Per2::luc); in vivo Per2 expression rhythms in the bladder of Per2::luc mice. Control mice did not show altered urination behavior in the light phase, whereas RS mice exhibited a higher voiding frequency and lower bladder capacity. In the bladder mucosa, RS mice also showed abrogated or misaligned Piezo1 , TRPV4 , Connexin26 , and clock gene expression. The rhythmic expression of Per2 was also altered in RS mice both in excised- and in vivo bladder, compared with control mice. After PF administration, voiding frequency was reduced and bladder capacity was increased during the light phase in RS mice; the in vivo Per2 expression rhythm was also fully restored. Therefore, RS can alter circadian gene expression in the bladder during the light phase and might cause nocturia via changes in circadian bladder function due the dysregulation of clock genes. Amending the circadian rhythm therapeutically could be applied for nocturia.

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“…Detailed information about the participants and their FVC data was provided previously. 13 Serum sampling and preparation Blood samples of 3 ml from fasting participants were acquired at the outpatient clinic of our department between 0800 and 0900 and stored at −80°C. A plasma volume of 50 µl was added to 450 µl of methanol containing internal standards and mixed.…”

Section: Participantsmentioning

confidence: 99%

Metabolomics analysis of blood identifies potential biomarkers and possible treatment targets for nocturia

Kira

Mitsui

Miyamoto

et al. 2019

Therapeutic Advances in Urology

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Background: Our aim was to investigate the association between serum metabolites and nocturia. Methods: A total of 66 males aged 65–80 years were enrolled in this study and stratified according to micturition behavior, which was characterized in terms of the 24 h frequency volume chart (FVC) for 3 consecutive days, the International Prostate Symptom Score (IPSS), and quality-of-life score. The nocturia group included participants with any total IPSS and ⩾1.5 micturitions/night as the mean of 3 nights, while the control group included participants with total IPSS < 8 and <1.5 micturitions/night. We conducted a comprehensive capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) study of plasma metabolites. Between-group comparisons of metabolite levels employed the Welch t test. The relationship between nocturia and metabolite profiles was determined using multivariable logistic regression analysis. Results: Of 66 participants, 45 were included in the nocturia group and 21 in the control group. There were no differences in background factors between the two groups. FVC analysis revealed that urine production during night-time, as well as micturition frequency during daytime and night-time were significantly higher in the nocturia group. CE-TOFMS identified eight metabolites whose plasma levels differed between the two groups. Multivariate analysis indicated that increased levels of lauric acid and imidazolelactic acid, as well as decreased levels of thiaproline and glycerol, contribute to the etiology of nocturia in aged men. Conclusions: Our findings suggest that abnormal serum levels of metabolites in several pathways play a role in the pathogenesis of nocturia in aged men.

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Lack of Change in the Adaptation Ability of the Bladder for the Urine Production Rate in Aged Men with Nocturia

Cited by 4 publications

References 15 publications

Effects of fatty acid metabolites on nocturia

Effects of fatty acid metabolites on nocturia

Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia

Metabolomics analysis of blood identifies potential biomarkers and possible treatment targets for nocturia

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